In the past 25 years, scientists have studied Alzheimer's disease from many angles. They've looked at populations to see how many cases of AD occur and whether there might be links between the disease and lifestyles or genetic backgrounds. They've conducted clinical studies with healthy older people and those at various stages of AD. They've examined individual nerve cells to see how beta-amyloid and other molecules affect the ability of cells to function normally.

These studies have led to better diagnostic tests, new ways to manage behavioral aspects of AD, and a growing number of possible drug treatments. Findings from current research are pointing scientists in promising directions for the future. They are also helping researchers ask better questions about the issues that are still unclear.

Part 2 of Unraveling the Mystery describes what we're learning from our search for:

• The causes of AD
• New techniques to help in diagnosis
• New treatments
• Ways to improve support for families and other caregivers

Results from this research will bring us closer to the day when we will be able to prevent or even cure the devastating disease that robs our older relatives and friends of their most precious possession - their minds.

One of the most important parts of unraveling the AD mystery is finding out what causes the disease. What makes the disease process begin in the first place? What makes it worse over time? Why does the number of people with the disease increase with age? Why does one person develop it and another remain healthy?

Some diseases, like measles or pneumonia, have clear-cut causes. They can be prevented with vaccines or cured with antibiotics. Others, such as diabetes or arthritis, develop when genetic, lifestyle, and environmental factors work together to cause a disease process to start. The importance of each one of these factors may be different for each individual.

AD fits into this second group of diseases. We don't yet fully understand what causes AD, but we know it develops because of a complex series of events that take place in the brain over a long period of time. Many studies are exploring the factors involved in the cause and development of AD.

Genetic Factors at Work in AD In the last few years, painstaking detective work by scientists has paid off in discoveries of genetic links to the two main types of AD. One type is the more rare, early-onset Alzheimer's disease. It usually affects people aged 30 to 60. Some cases of early-onset disease are inherited and are called familial AD (FAD). The other is late-onset Alzheimer's disease. It is the most common form and occurs in those 65 and older

DNA, Chromosomes, and Genes: The Body's Amazing Control Center Click here for larger view The nucleus of almost every human cell contains a vast chemical information database. This database carries all the instructions the cell needs to do its job. This database is DNA. DNA exists as two long, intertwined, thread-like strands packaged in units called chromosomes. Each cell has 46 chromosomes in 23 pairs. Chromosomes are made up of four chemicals, or bases, arranged in various sequence patterns. People inherit material in each chromosome from each parent. Each chromosome has many thousands of segments, called genes. The sequence of bases in a gene tells the cell how to make specific proteins. Proteins determine the physical characteristics of living organisms. They also direct almost every aspect of the organism's construction, operation, and repair. Even slight alterations in a gene can produce an abnormal protein, which, in turn, can lead to cell malfunction, and eventually, to disease. Any rare change in a gene's DNA that causes a disease is called a mutation. Other more common (or frequent) changes in a gene's DNA don't automatically cause disease, but they can increase the chances that a person will develop a particular disease. When this happens, the changed gene is called a genetic risk factor.

Genes and Early-onset Alzheimer's Disease

Even though early-onset AD is very rare and mutations in these three genes do not play a role in the more common late-onset AD, these findings were crucial because they showed that genetics was indeed a factor in AD, and they helped to identify some key players in the AD disease process. Importantly, they showed that mutations in APP can cause AD, highlighting the key role of beta-amyloid in the disease. Many scientists believe that mutations in each of these genes cause an increased amount of the damaging beta-amyloid to be made in the brain.

The findings also laid the foundation for many other studies that have pushed back the boundaries of our knowledge and created new possibilities for future treatment. For example, in the last several years, a series of highly sophisticated experiments have shown that presenilin may actually be one of the enzymes (substances that cause or speed up a chemical reaction) that clips APP to form beta-amyloid (the protein fragment that is the main component of AD plaques). This discovery has helped clarify how presenilins might be involved in the early stages of AD. It has also given scientists crucial new targets for drug therapy and has spurred many new studies in the test tube, in animals, and even in people.

A Different Genetic Story in Late-onset Alzheimer's Disease While some scientists were focused on the role of chromosomes 21, 14, and 1 in early-onset AD, others were looking elsewhere to see if they could find genetic clues for the late-onset form. By 1992, these investigators had narrowed their search to a region of chromosome 19. At the same time, other colleagues were looking for proteins that bind to beta-amyloid. They were hoping to clarify some of the steps in the very early stages of the disease process. They found that one form of a protein called apolipoprotein E (ApoE) did bind quickly and tightly to beta-amyloid. They also found that the gene that produces ApoE was located in the same region of chromosome 19 pinpointed by the geneticists. This finding led them to suggest that one form of this gene was a risk factor for late-onset Alzheimer's disease.

Other studies since then have shown that the gene that produces ApoE comes in several forms, or alleles - e2, e3, and e4. The APOE e2 allele is relatively rare and may provide some protection against the disease. If AD does occur in a person with this allele, it develops later in life. APOE e3 is the most common allele. Researchers think it plays a neutral role in AD. APOE e4 occurs in about 40 percent of all AD patients who develop the disease in later life. It is not limited to people whose families have a history of AD, though. AD patients with no known family history of the disease are also more likely to have an APOE e4 allele than persons who do not have AD. Dozens of studies have confirmed that the APOE e4 allele increases the risk of developing AD. These studies have also helped to explain some of the variation in the age at which AD develops. However, inheriting an APOE e4 allele doesn't mean that a person will definitely develop AD. Some people with one or two APOE e4 alleles never get the disease and others who do develop AD do not have any APOE e4 alleles.

Although we still don't exactly know how APOE e4 increases AD risk, one theory is that when its protein product binds quickly and tightly to beta-amyloid, the normally soluble amyloid becomes insoluble. This may mean that it is more likely to be deposited in plaques.

While scientists are working to understand more fully the APOE gene and its role in AD, they have also identified regions on other chromosomes that might contain genetic risk factors. For example, in 2000, three teams of scientists, using three different strategies, published studies showing that chromosome 10 has a region that may contain several genes that might increase a person's risk of AD. Identifying these genes is one important step in the research process that will lead to new understanding about the ways in which changes in protein structures cause the disease process to begin and the sequence of events that occurs as the disease develops. Once they understand these processes, scientists can search for new ways to diagnose, treat, or even prevent AD.

Other Factors at Work in AD Even if genetics explains some of what might cause AD, it doesn't explain everything. So, researchers have looked at other possibilities that may reveal how the Alzheimer's disease process starts and develops.

Beta-amyloid We still don't know whether beta-amyloid plaques cause AD or whether they are a by-product of the disease process. We do know, however, that forming beta-amyloid from APP is a key process in AD. That's why finding out more about beta-amyloid is an important avenue of ongoing AD research. Investigators are studying:

• The nature of beta-amyloid
• Ways in which it is toxic to neurons
• Ways in which plaques form and are deposited
• Ways in which beta-amyloid and plaques might be reduced in the brain

Tau In the last few years, scientists have been giving an increasing amount of attention to tau, the other hallmark of Alzheimer's disease. This protein is commonly found in nerve cells throughout the brain. In AD, tau undergoes changes that cause it to gather together abnormally in tangled filaments in neurons (for more on this, see the section A Walking Tour Through the Brain). In studying tau and what can go wrong, investigators have found that tau abnormalities are also central to other rare neurodegenerative diseases. These diseases, called tauopathies, include frontotemporal dementia, Pick's disease, supranuclear palsy, and corticobasal degeneration. They share a number of characteristics, but also each have distinct features that set them apart from each other and from AD. Characteristic signs and symptoms include changes in personality, social behavior, and language ability; difficulties in thinking and making decisions; poor coordination and balance; psychiatric symptoms; and dementia. Recent advances include the discovery of mutations in the tau gene that cause one tauopathy called frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). The development of several mouse models that produce tau tangles, will allow researchers to address the many questions that remain about these diseases. The development of a "double transgenic" mouse that has both tau tangles and beta-amyloid plaques will also lead to further insights about AD.

Cardiovascular Risk Factors Several recent studies in populations have found a possible link between factors related to cardiovascular disease and AD. One of these studies found that elevated levels of an amino acid called homocysteine, a risk factor for heart disease, are associated with an increased risk of developing AD. The relationship between AD and homocysteine is particularly interesting because blood levels of homocysteine can be reduced by increasing intake of folic acid and vitamins B6 and B12. In fact, in other studies, scientists have shown that folic acid may protect against nerve cell loss in brain regions affected by AD. Investigators have also found that the use of statins, the most common type of cholesterol-lowering drugs, is associated with a lower risk of developing AD.

Oxidative Damage from Free Radicals Another promising area of investigation relates to a longstanding theory of aging. This theory suggests that over time, damage from a kind of molecule called a free radical can build up in neurons, causing a loss in function. Free radicals can help cells in certain ways, such as fighting infection. However, too many can injure cells because they are very active and can readily change other nearby molecules, such as those in the neuron's cell membrane or in DNA. The resulting molecules can set off a chain reaction, releasing even more free radicals that can further damage neurons. This kind of damage is called oxidative damage. It may contribute to AD by upsetting the delicate machinery that controls the flow of substances in and out of the cell. The brain's unique characteristics, including its high rate of metabolism and its long-lived cells, may make it especially vulnerable to oxidative damage over the lifespan. Some epidemiological and laboratory studies suggest that anti-oxidants from dietary supplements or food may provide some protection against developing AD. Other studies suggest that low calorie diets may protect against the development of AD by slowing down metabolic rates.

Inflammation Another set of hints about the causes of AD points to inflammation in the brain. This process is part of the immune system and helps the body react to injury or disease. Fever, swelling, pain, or redness in other parts of the body are often signs of inflammation. Because cells and compounds that are known to be involved in inflammation are found in AD plaques, some researchers think it may play a role in AD.

They disagree, though, on whether inflammation is a good or a bad thing. Some think it is harmful - that it sets off a vicious cycle of events that ultimately causes neurons to die. Evidence from many studies supports this idea.

Other scientists believe that some aspects of the inflammatory process may be helpful - that they are part of a healing process in the brain. For example, certain inflammatory processes may play a role in combating the accumulation of plaques. Many studies are now underway to examine the different parts of the inflammatory process more fully and their effects on AD.

Brain Infarction We've all heard the sensible advice about ways to live a long and healthy life: eat right, exercise, don't smoke, wear a seat belt. All of these habits can help prevent heart attacks, stroke, and injuries. This advice may even have some relevance for AD as well. Results from one long-term study of aging and AD show that participants who had evidence of stroke in certain brain regions had more symptoms of dementia than could be explained by the number of plaques and tangles in their brain tissue. These findings suggest that damage to blood vessels in the brain may not be enough to cause AD, but that it could make AD clinical symptoms worse.